This application is the National Stage of International Patent Application Ser. No. PCT/JP98/01871, filed Apr. 23, 1998.
The present invention relates to amide derivatives exhibiting excellent cell differentiation-inducing actions or cell differentiation-inducing action-enhancing actions such as bone morphogenetic protein (BMP) action or BMP-enhancing action or neurotrophic factor (NTF) actions (e.g., nerve growth factor (NGF) action, brain-derived neurotrophic factor (BDNF) action, neurotrophin-3 (NT-3) action and glial cell line-derived neurotrophic factor (GDNF) action) or NTF-enhancing action, a method of their production and a pharmaceutical composition containing them.
Bone morphogenetic protein (BMP), isolated from demineralized bone, is the only group of protein factors known to be capable of ectopic bone induction. It is therefore useful as an osteogenesis promoter in bone fracture healing, bone reconstruction etc. (A. E. Wang, Trends in Biotechnology, Vol. 11, pp. 379-383 (1993)).
To date, a number of such substances with BMP action-enhancing activity have been reported, i.e., retinoic acid, vitamin D3, estrogen and glucocorticoid (V. Rosen and R. S. Thies, Trends in Genetics, Vol. 8, pp. 97-102 (1992); Y. Takuwa et al., Biochemical and Biophysical Research Communications, Vol. 174, pp. 96-101 (1991)).
Also, because BMP directly promotes osteoblast differentiation, it is assumed to play a role as a coupling factor in bone remodelling, and is thought to be closely involved in bone metabolism. Also, it has been reported that the BMP content in bone substrate in aged animals has been considerably decreased (M. L. Urist, Bone and Mineral Research, Vol. 6 (ed. by W. A. Peck), pp. 57-112, Elsevier, 1989), suggesting that BMP is profoundly involved in the maintenance of bone mass. This suggests that BMP is promising as a therapeutic drug for various bone diseases such as osteoporosis. However, because BMP is normally present in trace amounts in living body so that its supply is limited, and because BMP is a protein so that a problem arises in its administration, the target diseases to which it is applicable are limited.
In addition, BMP has been reported to possess an activity like that of neurotrophic factors (V. M. Paralkar et al., Journal of Cell Biology, Vol. 119, pp. 1,721-1,728 (1992)). Also, it is known that the BMP gene is strongly expressed in brain tissue (E. Ozkaynak et al., Biochemical and Biophysical Research Communications, Vol. 179, pp. 116-123 (1991)). Also, BMP has been suggested as playing an important role in neural tube formation in embryogenesis (K. Basler et al., Cell. Vol. 73, pp. 687-702 (1993)).
Neurotrophic factors, a group of proteinous factors playing an important role in the survival and functional expression of neurons, include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF). NGF promotes the differentiation and maturation of the sympathetic ganglion cells and dorsal root ganglion cells of the neural tube in the peripheral nervous system (A. M. Davies and R. M. Lindsay, Developmental Biology, Vol. 111, pp. 62-72 (1985); R. Levi-Montalcini, EMBO Journal, Vol. 6, pp. 1,145-1,154 (1987)), and acts on the cholinergic neurons of septa (procephalic basal ganglia) in the central nervous system (H. Gnahn et al., Developmental Brain Research, Vol. 9, pp. 45-52 (1983); H. Hatanaka and H. Tsukui, Developmental Brain research, Vol. 30, pp. 47-56 (1986); F. Hefti, Journal of Neuroscience, Vol. 6, pp. 2,155-2,162 (1986)). NGF is essential for the maintenance of nervous function even after completion of neuron differentiation. BDNF acts on the dorsal spinal root ganglion cells and nodal ganglion cells in the peripheral nervous system but does not act on sympathetic ganglion cells (R. M. Lindsay and H. Rohrer, Developmental Biology, Vol. 112, pp. 30-48 (1985); R. M. Lindsay et al., Developmental Biology, Vol. 112, pp. 319-328(1985); A. M. Davies et al., Journal of Neuroscience, Vol. 6, pp. 1,897-1,904 (1986)). On the other hand, in the central nervous system, BDNF acts on the cholinergic neurons and GABA (xcex3-aminobutyric acid)-acting neurons of septa, and the dopaminergic neurons of the mesencephalon (R. F. Alderson et al., Neuron, Vol. 5, pp. 297-306 (1990); C. Hyman et al., Nature, Vol. 350, pp. 230-232 (1991); B. Knusel et al., Proceedings of the National Academy of Sciences of the United States of America, Vol. 88, pp. 961-965 (1991)). NT-3 is characterized by potent action on the sensory neurons derived from the neural plate, although its action overlaps those of NGF and BDNF in the peripheral nervous system (P. Ernfors et al., Proc. Natl. Acad. Sci. USA, Vol. 87, pp. 5,454-5,458 (1990); A. Rosenthal et al., Neuron, Vol. 4, pp. 767-773 (1990)). However, there are no known neurons of the central nervous system that respond to NT-3.
As a substance exhibiting NGF action, sabeluzole [4-(2-benzothiazolylmethylamino)-xcex1(p-fluorophenoxy)methyl]-1-(piperidine) ethanol] has been reported (New Current, Vol. 4, No. 26, p. 14 (1993)]; in addition, SR57746A [Neuroscience, Vol. 55, p. 629 (1993)), T-588 (Japanese Patent Unexamined Publication No. 95070/1992) and MS430 (Journal of University of Occupational and Environmental Health, Vol. 17, p. 131 (1995)) have also been reported to enhance NGF action. Also, as compounds exhibiting NGF secretion-inducing action, steroids, catechols and cytokines have been reported (Experimental Neurology, Vol. 124, pp. 36-42 (1993)).
Alzheimer dementia has been characterized by extensive lesion and exfoliation of cerebrial cortical neurons, as well as degeneration and exfoliation of cholinergic neurons of the basal ganglia, including the septal area; NGF and new neurotrophic factors are considered as candidates for therapeutic drugs therefor (F. Hefti and W. J. Weiner, Annual Neurology, Vol. 20, pp. 275-281 (1986)). Because these neurothrophic factors are proteins, however, their application are subject to limitation.
Also, low-molecular compounds known to promote osteoblast proliferation and differentiation include, for example, ipriflavone (K. Notoya et al., Journal of Bone and Mineral Research, Vol. 9, pp. 395-400 (1994)) and vitamin K2 (Y. Akedo et al., Biochemical and Biophysical Research, Vol. 187, pp. 814-820 (1992)) but these do not possess ectopic bone induction capability as does BMP.
Compounds known to exhibit actions like those of neurotrophic factors, such as the extension of neurites and neuron survival, include lactastatin (S. Omura et al., Journal of Antibiotics, Vol. 40, pp. 113-117 (1991)), retinoic acid (M. Minana et al., Proceedings of the National Academy of Science of the USA, Vol. 876, pp. 4335-4339 (1990)), staurosporin (T. B. Shea et al. Journal of Neuroscience Research, Vol. 33, pp. 398-407 (1990)), K252a (G. D. Borasio et al., Neuroscience Letters, Vol. 108, pp. 207-212 (1990)), and MS818 (A. Awaya et al., Biological and Pharmaceutical Bulletin, Vol. 16, pp. 248-253 (1993)).
(1) A naphthalenecarboxamide represented by the formula: 
wherein Ar1 represents allylene-(R8)2 (R8: a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy etc.); Ar2 represents aryl-(R9)2 (R9: a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy etc.); R1 represents a hydrogen atom, lower alkyl, hydroxy or lower alkoxy; R2 represents a hydrogen atoms, lower alkyl or a group which forms xe2x95x90O in cooperation with R1; R3 represents a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy or the like; R4 represents a hydrogen atom or lower alkyl; R7 represents a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy or the like; each of R10 and R11 represents a hydrogen atom, halogen, lower alkyl, hydroxy, a lower alkoxy, CON(R16)2 (R16 represents a hydrogen atom, lower alkyl or OR13 (R13 is a hydrogen atom or lower alkyl)) or the like; is disclosed in U.S. Pat. No. 5,308,852;
(2) a compound represented by the formula: 
wherein R represents a hydrogen atom, acetyl or methyl, is disclosed in Japanese Patent Unexamined Publication No. 153625/1991; and
(3) a compound represented by the formula: 
is disclosed in Heterocycles, Vol. 38, pp. 103-111 (1994), etc.
However, the publications disclosing the carboxamide compounds (1) to (3) above give no description of cell differentiation-inducing action or cell differentiation-inducing factor action-enhancing action, bone morphogenetic protein (BMP) action or BMP action-enhancing action, neurotrophic factor (NTF) action or NTF action-enhancing action.
In view of the above aspects, any compounds which enhance BMP action, for example, would enhance the action of BMP present in vivo or administered to the living body and would be useful as a therapeutic drug for bond diseases as described above. However, conventional substances, when administered in vivo, are known to promote bone resorption and have side effects such as hypercalcemia and ovarian cancer onset, and are not always appropriate for use as therapeutic drugs for bone diseases.
On the other hand, any compounds which enhance the action of NGF, for example, would enhance the action of NGF present in vivo or administered to the living body and would be useful as a therapeutic drug for dementia and peripheral neuropathy; however, their action mechanism remains to be clarified; clinical studies have demonstrated some such substances have side effects such as headache, dizziness and fatigue, others remain to be proven effective in humans, others possess insufficient activity, others possess nervous toxicity, and others exhibit pharmaceutically undesirable actions such as immunity reduction, hypercalcemia and boner resorption promotion, so they are unsatisfactory for practical application.
Moreover, because cell differentiation induction factors represented by BMP or neurotrophic factors are proteins, their administration to the living body are subject to limitation. Compounds which enhance the action of cell differentiation induction factors present in vivo or administered to the living body are therefore preferably of low molecular weight.
Also, even if the compound itself possesses cell differentiation induction factor action, as exemplified by BMP and neurotrophic factors, provided that is of low molecular weight, it is believed to serve advantageously over BMP and neurotrophic factors in terms of administration to the living body, and other aspects, as an osteogenesis promoter in bone fracture healing and bone reconstruction, and as a therapeutic drug for dementia and peripheral neuropathy.
In other words, conventional compounds that act like neurothrophic factors, as well as enhance their action, have not been proven to be effective in humans, and other compounds are unsatisfactory for practical application in terms of activity potency, toxicity, etc.
There is therefore strong demand for the development of compounds differing from the above-described known substances, possession excellent BMP action or neurotrophic factor action or enhancing such action, and serving well as a pharmaceutical.
Against this technical background, the present inventors made extensive investigation, and for the firs time succeeded in creating a compound characterized by a unique chemical structure with a carbamoyl group xe2x80x94COR1 which may be substituted, and represented by the formula: 
wherein R1 is an amino group which may be substituted; R2 is a hydrogen atom or a lower alkyl group which may be substituted; X is a methine group which may be substituted or N(O)m (m is 0 or 1); a ring a is a homo- or hetero-cycle which is substituted by a halogen atom, lower alkyl, lower alkoxy or lower alkylenedioxy group; and a ring B is a homo- or hetero-cycle which may be substituted; or a salt thereof, and found that this compound, represented by formula (I), or a salt thereof unexpectedly exhibits BMP or neurotrophic factor action, specifically enhances the actions of BMP and neurotrophic factors, such as osteoblast and neuron differentiation and neuron survival, and is a low-molecular compound useful as an agent for inducing a cell differentiation or enhancing an action of induction factor of cell differentiation etc., and is fully satisfactory as a pharmaceutical. The present inventors made further investigation based on this finding, and developed the present invention.
The present invention provides:
(1) A compound represented by the formula: 
wherein R1 is an amino group which may be substituted; R2is a hydrogen atom or a lower alkyl group which may be substituted; X is a methyne group which may be substituted or N(O)m (m is 0 or 1); a ring A is a homo- or hetero-cycle which is substituted by a halogen atom, lower alkyl, lower alkoxy or lower alkylenedioxy; and a ring B is a homo- or hetero-cycle which may be substituted; or a salt thereof,
(2) The compound as defined in (1) wherein R1 is
(I) an amino group which may be substituted by
(a) a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group or C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkyl amino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl amino and C1-6 alkylsulfonyl amino, (xvii) C1-6 alkylcarbonyl, (xviii) carboxyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoyl, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi) C6-10 aryl and (xvii) C6-10 aryloxy,
(b) a hydroxy group which may be substituted by a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group or C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkyl amino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl amino and C1-6 alkylsulfonyl amino, (xvii) C1-6 alkylcarbonyl, (xviii) carboxyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoyl, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi) C6-10 aryl and (xxvii) C6-10 aryloxy, or
(c) an amino group which may be substituted by an acyl group represented by any one of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R7, xe2x80x94SO2xe2x80x94R7, xe2x80x94SOxe2x80x94R7, xe2x80x94(Cxe2x95x90O)NR8R7, xe2x80x94(Cxe2x95x90O)Oxe2x80x94R7, xe2x80x94(Cxe2x95x90S)Oxe2x80x94R7 or xe2x80x94(Cxe2x95x90S)NR8R7 wherein R7 is (a) hydrogen atom or (b) a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group or C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkyl amino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl amino and C1-6 alkylsulfonyl amino, (xvii) C1-6 alkylcarbonyl, (xviii) carbonyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoyl, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi) C6-10 aryl and (xxvii) C6-10 aryloxy, and R8 is hydrogen atom or a C1-6 alkyl group, or
(II) a group formed by removing a hydrogen atom from a nitrogen atom of a 5 to 9 membered nitrogen-containing heterocycle which may have 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, other than carbon atoms and one nitrogen atom, and the nitrogen-containing heterocycle may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkyl amino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl, (xviii) carboxyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoyl, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi) C6-10 aryl and (xxvii) C6-10 aryloxy; R2 is (a) a hydrogen atom or (b) a C1-6 alkyl group which may be substituted by a group selected from that consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkyl amino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl amino and C1-6 alkylsulfonyl amino, (xvii) C1-6 alkylcarbonyl, (xviii) carboxyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoyl, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi) C6-10 aryl and (xxvii) C6-10 aryloxy; X is N(O)m (m is 0 or 1) or CR6xe2x80x2 wherein R6xe2x80x2 is
(a) a hydrogen atom,
(b) a halogen atom,
(c) a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group or C7-16 aralkyl group which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkyl amino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl amino and C1-6 alkylsulfonyl amino, (xvii) C1-6 alkylcarbonyl, (xviii) carboxyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoyl, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi) C6-10 aryl and (xxvii) C6-10 aryloxy or
(d) xe2x80x94OR6xe2x80x3 wherein R6xe2x80x3 is (axe2x80x2) a hydrogen atom or (bxe2x80x2) a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group or C7-16 aralkyl group which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkyl amino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl amino and C1-6 alkylsulfonyl amino, (xvii) C1-6 alkylcarbonyl, (xviii) carboxyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoyl, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi) C6-10 aryl and (xxvii) C6-10 aryloxy; the ring a is a 3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than carbon atoms, and the 3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocycle is substituted by a halogen atom, C1-6 alkyl, C1-6 alkoxy or C1-3 alkylenedioxy, and adjacent substituents of the ring A may combine with each other and form a 3 to 10 membered cyclic hydrocarbon; and
the ring B is a 3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than carbon atoms, and the 3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocycle may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkyl amino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl amino and C1-6 alkylsulfonyl amino, (xvii) C1-6 alkylcarbonyl., (xviii) carbonyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoyl, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi) C6-10 aryl and (xxvii) C6-10 aryloxy,
(3) the compound as defined in (1) wherein R1 is a group represented by the formula: 
wherein R3 and R4 is the same or different and are independently a hydrogen atom, a hydroxy group which may be substituted, a lower alkyl group which may be substituted, an acyl group, an aryl group which may be substituted or an aralkyl group which may be substituted, or R3 and R4 may combine with an adjacent nitrogen atom and form a nitrogen-containing heterocyclic group which may be substituted,
(4)The compound as defined in (3) wherein R3 and R4 is the same or different and are independently a hydrogen atom, a hydroxy group which may be substituted, a lower alkyl group which may be substituted or an acyl group, or R3 and R4may combine with an adjacent nitrogen atom and form a nitrogen-containing heterocyclic group which may be substituted,
(5) The compound as defined in (3) wherein R3 and R4 is the same or different and are independently a hydrogen atom or a lower alkyl group which may be substituted,
(6) The compound as defined in (3) wherein R3 is a hydrogen atom or a C1-6 alkyl group, and R4 is (i) a hydrogen atom or (ii) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carboxyl, C1-6 alkoxy-carbonyl, amino and mono- or di-C1-6 alkyl amino, (iii) a C6-14 aryl group which may be substituted by C1-6 alkoxy or (iv) a C7-16 aralkyl group which may be substituted by C1-6 alkoxy or C1-6 acylamino, or R3 and R4 combine with an adjacent nitrogen atom and form a 5 to 8 membered nitrogen-containing heterocyclic group which may be substituted by C7-16 aralkyl,
(7) The compound as defined in (1) wherein R2 is a hydrogen atom or a lower alkyl group which may be substituted,
(8) The compound as defined in (1) wherein R2 is (i) a hydrogen atom or (ii) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carbamoyl optionally having C1-6 alkyl and amino optionally having C1-6 alkyl,
(9) The compound as defined in (1) wherein X is a methyne group which may be substituted,
(10) The compound as defined in (1) wherein X is a methyne group which may be substituted by C1-6 alkyl,
(11) The compound as defined in (1) wherein X is N(O)m (m is 0 or 1),
(12) The compound as defined in (1) wherein X is N,
(13) The compound as defined in (1) wherein the ring A is a benzene ring which is substituted by a halogen atom, lower alkyl, lower alkoxy or lower alkylenedioxy,
(14) the compound as defined in (1) wherein the ring A is a C6-12 aromatic hydrocarbon ring which is substituted by a group selected from the group consisting of a halogen atom, C1-6 alkyl, C1-6 alkoxy and C1-3 alkylenedioxy,
(15) The compound as defined in (1) wherein the ring B is a benzene ring which may be substituted,
(16) The compound as defined in (1) wherein the ring B is (i) a C6-12 aromatic hydrocarbon ring which may be substituted by a group selected from the group consisting of a halogen atom, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy and C1-3 alkylenedioxy or, (ii) a 5 to 8 membered heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms, and the 5 to 8 membered heterocycle may be substituted by C1-6 alkyl,
(17) The compound as defined in (1) wherein R1 is a group represented by the formula: 
wherein
R3xe2x80x2 is a hydrogen atom or C1-6 alkyl group, and
R4xe2x80x2 is (i) a hydrogen tom, (ii) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carboxyl, C1-6 alkoxy-carbonyl, amino and mono- or di-C1-6 alkylamino, (iii) a C6-14 aryl group which may be substituted by C1-6 alkoxy or (iv) a C7-16 aralkyl group which may be substituted by C1-6 alkoxy or C1-6 acylamino, or R3xe2x80x2 and R4xe2x80x2 may combine with an adjacent nitrogen atom and form a 5 to 8 membered nitrogen-containing heterocyclic group which may be substituted by C7-16 aralkyl;
R2 is (i) a hydrogen atom or (ii) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carbamoyl optionally have C1-6 alkyl and amino optionally having C1-6 alkyl;
X is a methyne group which may be sustituted by C1-6 alkyl or N(O)m (m is 0 or 1);
the ring A is C6-12 aromatic hydrocarbon ring which is substituted by a group selected from the group consisting of a halogen atom, C1-6 alkyl, C1-6 alkoxy and C1-3 alkylenedioxy; and
the ring B is (i) a C6-12 aromatic hydrocarbon ring which may be substituted by a group selected from the group consisting of a halogen atom, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy and C1-3 alkylenedioxy or (ii) a 5 to 8 membered heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen a tom and a sulfur atom other than carbon atoms, and the 5 to 8 membered heterocycle may be substituted by C1-6 alkyl,
(18) The company as defined in (1) wherein R1 is a group represented by the formula: 
wherein R3xe2x80x3 is a hydrogen atom and R4xe2x80x3 is a hydrogen atom or C7-16 aralkyl group which may be substituted by C1-6 alkoxy; R2 is a hydrogen atom or C1-6 alkyl group which may be substituted by hydroxy; X is a methyne group or N; the ring A is a C6-12 aromatic hydrocarbon ring which is substituted by C1-6 alkoxy or C1-3 alkylenedioxy; and the ring B is a C6-12 aromatic hydrocarbon ring which may be substituted by a group selected from the group consisting of a halogen atom, C1-6 alkoxy and C1-3 alkylenedioxy,
(19)N-methyl-9-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-naphtho [1,2-d]-1,3-dioxole-6-carboxamide or a salt thereof,
(20) N-methyl-8-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-naphtho [2,3-d]-1,3-benzodioxole-6-carboxamide or a salt thereof,
(21) 9-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-1,3-dioxolo [4,5-f]quinoline-7-carboxamide or a salt thereof,
(22) N-methyl-4-(1,3- benzodioxole-5-yl)-6,7-diethoxy-3-hydroxymethyl-naphthalene-2-carboxamide or a salt thereof,
(23) 9-(4-methoxyphenyl)-N-[(4-methoxyphenyl)menthyl]-1,3-dioxolo [4,5-f]quinoline-7-carboxamide or a salt thereof,
(24) 9-(1,3-benzodioxole-5-yl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo [4,5-f]quinoline-7-carboxamide or a salt thereof,
(25) 9-(4-fluorophenyl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide or a salt thereof,
(26) A method for producing a compound represented by the formula: 
wherein R11 is a lower alkyl group which may be substituted and other symbols are same as defined in (1), or a salt thereof which comprises subjecting a compound represented by the formula: 
wherein each symbol is a same as defined in (1), or a salt thereof to a functional group-converting reaction or/and a carbon-adding reaction,
(27) A method for producing the compound as defined in (1) or a ester thereof, or a salt thereof which comprises subjecting a compound represented by the formula: 
wherein each symbol is same as defined in (1), or a salt thereof to an amidating reaction, and if desired followed by a acylating reaction,
(28) A pharmaceutical composition which comprises the compound as defined in (1) or a salt thereof,
(29) An agent for inducing a cell differentiation or enhancing an action of induction factor of cell differentiation which comprises a compound represented by the formula: 
wherein a ring Axe2x80x2 is a homo- or hetero-cycle which may be substituted and other symbols are same as defined in (1),
(30) The agent as defined in (29) wherein the ring Axe2x80x2 is (a) 3 to 10 membered cyclic hydrocarbon or (b) a 5 to 9 membered heterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than carbon atoms, and the 3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocycle may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6alkynyl, (viii) C3-6 cycloalkyl, (ix) optionally halogenated C1-6 alkoxy, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkyl amino, (xv) 5 or 6 membered cyclic amino, *xvi) acyl amino selected from C1-6 alkoxy-carbonyl amino, mono-C1-6 alkylaminocarbonyl amino, C1-6 alkylcarbonyl amino and C1-6 alkylsulfonyl amino, (xvii) C1-6 alkylcarbonyl, (xviii) carboxyl, (xix) C1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C1-6 alkyl-carbamoly, (xxii) di-C1-6 alkyl-carbamoyl, (xxiii) C6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C1-6 alkyl sulfonyl, (xxvi)c6-10 aryl and (xxvii) C6-10 aryloxy; or adjacent substituents of the ring Axe2x80x2 may combine with each other and form (a) a 3 to 10 membered cyclic hydrocarbon, (b) a 3 to 9 membered aromatic heterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than carbon atoms or (c) a 5 to 9 non-aromatic heterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than carbon atoms,
(31) The agent as defined in (28) which is an agent for treating or preventing nerve diseases or bone/joint diseases,
(32) The agent as defined in (31) wherein the nerve disease is a disease based on nerve degeneration in cerebrovascular dementia, senile dementia or Alzheimer""s disease; amyotrophic lateral aclerosis; diabetic peripheral neuropathy; or Parkinson disease,
(33) A method for treating or preventing nerve diseases or bone/joint diseases which comprises administering an effective amount of the compound as defined (1) or a salt thereof to mammals,
(34) The method as defined in (33) wherein the nerve disease is a disease based on nerve degeneration in cerebrovascular dementia, senile dementia or Alzheimer""s disease; amyotrophic lateral aclerosis; diabetic peripheral neurotrophic lateral aclerosis; diabetic peripheral neuropathy; or Parkinson disease,
(35) Use of the compound as defined in (1) or a salt thereof for preparing an agent for treating or preventing nerve disease or bone/joint disease, and
(36) The use of defined in (35) wherein the nerve disease is a disease based on nerve degeneration in cerebrovascular dementia, senile dementia or Alzheimer""s disease; amyotrophic lateral aclerosis; diabetic peripheral neurotrophic laterial aclerosis; diabetic peripheral neuropathy; or Parkinson disease.
In the above mentioned formula, the ring A represents a homo- or hetero-cycle which is substituted by a halogen atom, lower alkyl, lower alkoxy or lower alkylenedioxy.
The homo- or hetero-cycle has any (preferably 1 to 5, more preferably 1 to 3) substituents as mentioned above at a position where it can be substituted. When a number of substituents are more than 2, each substituent may be same or different, and adjacent substituents may combine each other and form a ring.
When adjacent substituents of the ring A combine with each other and form a ring, examples of the ring are 3 to 10 membered cyclic hydrocarbon, preferably a 5 to 6 membered cyclic hydrocarbon. Specific examples of the ring are benzene, C3-10 cycloalkene (e.g. cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C3-10 cycloalkane (e.g. cyclobutane, cyclopentane, cyclohexane, cyclopheptane, cyclooctane, etc.), and so on. Preferable examples of the cycle are a 5 to 6 membered homocycle such as benzene, cyclopentane, cyclohexane, and more prefereable examples are a benzene ring.
When adjacent substituents of the ring A combine with each other and form a condensed ring with the ring A, examples of the condensed ring are naphtharene, and so on.
In the above mentioned formula, the homocycle represented by the ring A means a cyclic hydrocarbon consisting of carbon atoms. Examples of the cyclic hydrocarbon are a 3 to 10 membered cyclic hydrocarbon, preferably a 5 to 6 membered cyclic hydrocarbon. Specific examples of the homocycle are benzene, C3-10 cycloalkene (e.g cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C3-10 cycloalkane (e.g. cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) and so on. Preferable examples are 5 to 6 membered homocycle such as benzene, cyclopentane, cyclohexane, and more preferable examples are a benzene ring and so on.
In the above mentioned formula, examples of the heterocycle represented by the ring A are an aromatic heterocycle or non-aromatic heterocycle containing more than 1 (e.g., 1 to 4, preferably 1 to 3) and one or two kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than carbon atoms, and so on.
Examples of the aromatic heterocycle are a 5 to 6 membered aromatic heterocycle containing 1 to 3 hetero atoms selected by a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms, such a a pyridine, pyrazine, pyrimidine, pyridazine, pyrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole ring, and so on. More preferable examples are a 6 membered nitrogen-containing heterocycle such as a pyridine, pyrazine, thiophene, pyrole, thiazole ring and so on. Particularly, a 6-membered nitrogen-containing heterocycle containing 1 or 2 nitrogen atoms other than carbon atoms (e.g. pyridine, pyrazine) is preferred.
Examples of the non-aromatic heterocycle are a 5 to 9 membered non-aromatic heterocycle, preferably a 5 to 6 membered non-aromatic heterocyle, containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms, and so on.
Specific examples of the non-aromatic heterocycle are a tetrahydropirdine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyrane, dihydropyrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofurane, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyrane, morphorine, pyrolodine, imidazolidide, pyrazoridine, tetrahydrorthiophene, tetrahydrofurane, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole ring and so on. Preferable examples are a 6 membered non-aromatic heterocycle containing 1 to 2 nitrogen atoms such as a tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, pyperidine, pyperazine ring, and more preferably examples are a pyperazine ring and so on.
In the homo- or hetero-cycle which is substituted by a halogen atom, lower alkyl, lower alkoxy or lower alkylenedioxy represented by the ring A,
(i) examples of the halogen atom are fluorine, chlorine, bromine and iodine
(ii) examples of the lower alkyl are a linear or branched C1-6 alkyl such as methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl, hexyl and so on, preferably methyl,
(iii) examples of the lower alkoxy are a linear or branched C1-6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, buthoxy, isobuthoxy, sec-buthoxy, tert-buthoxy and so on, preferably methoxy,
(iv) examples of the lower alkylenedioxy are a C1-3 alkylenedioxy such as methylendioxy, ethylendioxy, propylenedioxy and so on, preferably, ethylenedioxy.
Preferable examples of the ring A are a homocycle (preferably, a C6-12 aromatic hydrocarbon ring) which is substituted by a halogen atom, lower alkyl ( e.g. C1-6 alkyl), lower alkoxy (e.g. C1-6 alkoxy) or lower alkylenedioxy (e.g. C1-3 alkylenedioxy), and more preferable examples are a benzene ring which is substituted by a halogen atom, C1-6 alkyl, C1-6 alkoxy or C1-6 alkylenedioxy.
In the above mentioned formula, the ring Axe2x80x2 represents a homo- or hetero-cycle which may be substituted.
In the above mentioned formula, examples of the homocycle or heterocycle represented by the ring Axe2x80x2 are the homo- or hetero-cycle of the xe2x80x9chomo- or hetero-cycle which is substituted by a halogen atom, lower alkyl, lower alkoxy or lower alkylenedioxyxe2x80x9d represented by the ring A.
The homo- or hetero-cycle has any (preferably 1 to 5, more preferably 1 to 3) substiuents at a position where can be substituted. When a number of substituents are more than 2, each substituent may be same or different, and adjacent substituents may combine with each other and form a ring.
When adjacent substituents of the ring A combine with each other and form a ring, examples of the ring are
(i) a 3 to 10 membered cyclic hydrocarbon, preferably a 5 to 6 membered cyclic hydrocarbon,
(ii) a 3 to 9 membered aromatic heterocycle, preferably a 5 or 6 membered aromatic heterocycle containing more than 1 (e.g., 1 to 4, preferably 1 to 3) and one or two kinds of hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms, or
(iii) a 5 to 9 membered non-aromatich heterocycle, preferably a 5 or 6 membered non-aromatich heterocycle, containing more than 1 (e.g., 1 to 4, preferably 1 to 3) and one or two kinds of hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms and so on.
Specific examples of the 3 to 10 membered cyclic hydrocarbon in the above (i) are benzene, C3-10 cycloalkene (e.g. cyclobutene, cyclopentene, cyclohexane, cycloheptene, cyclootene, etc.), C3-10 cycloalkane (e.g. cyclobutane, cyclopetane, cyclohexane, cycloheptane, cyclootane, etc.), and so on. Preferable examples are 5 to 6 homocycle such as benzene, cyclopentane, an cyclohexane, and more preferable examples area benzene ring, and so on.
Examples of the aromatic heterocycle of the above (ii) are a 5 to 9 membered, preferably a 5 to 6 membered, aromatic heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms such as a pyridine, pyrazine, pyrimidine, pyridazine, pyrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole ring, and so on.
Examples of the non-aromatic heterocycle of the above (iii) area a 5 to 9 membered, preferably a 5 to 6 membered, non-aromatic heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms and so on. Specific examples of the non-aromatic heterocycle are a tetrahydropiridine, dihydropyridine, tetrahydropyradine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyrane, dihydropyrole, dihydromidazole, dihydropyrazole, dihydrothiophene, dihydrofurane, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydrioisoxanzone, piperidine, piperazine, hezahydropyrimidine, hexahydropyridazine, tetrahydrophyrane, morphorine, pyrrolidine, imidazolidide, pyrazoridine, tetrahydrorthiophene, tetrahydrofurane, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole ring, and so on.
When adjacent substituents of the ring Axe2x80x2 combine with each other and form a condensed ring with the ring Axe2x80x2, examples of the condensed ring are naphtharene, and so on.
In the above mentioned formula, examples of the substituents of the homo- or hetero-cycle represented by the ring Axe2x80x2 are
(i) a halogen atom (e.g. fluorine, chlorine, bromine, iodine),
(ii) lower alkylendedioxy (e.g. C1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy),
(iii) nitro,
(iv) cyano,
(v) optionally halogenated lower alkyl,
(vi) optionally halogenated lower alkenyl,
(vii) optionally halogenated lower alkynyl,
(viii) lower cycloalkyl (e.g. C3-6 cycloalkyl such as cyclopropyl, cyclobuthyl, cyclopenthyl, cyclohexyl),
(ix) optionally halogenated lower alkoxy,
(x) optionally halogenated lower alkylthio,
(xi) hydroxy,
(xii) amino,
(xiii) mono-lower alkylamino (e.g. mono-C1-6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, buthylamino),
(xiv) di-lower alkylamino (e.g. di-C1-6 alkyl amino such as dimethylamino, diethylamino, dipropylamino, dibuthylamino),
(xv) 5 or 6 membered cyclic amino (e.g. morpholino, pyperadine-1-yl, pyperidino, pyroridine-1yl,
(xvi) acyl amino
(xvii) lower alkyl-carbonyl (e.g. C1-6 alkyl-carbonyl such as acetyl, propyoyl),
(Xviii) carboxyl,
(xix) lower alkoxy-carbonyl (e.g. C1-6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propxycarbonyl, butoxycarbonyl),
(xx) carbamoyl,
(xxi) mono-lower alkyl-carbamoyl (e.g. mono-C1-6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl),
(xxii) di-lower alkyl-carbamoyl (e.g.di-C1-6 alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl),
(xxiii) aryl-carbamoyl (e.g. C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphtylcarbamoyl),
(xxiv) sulfo,
(xxv) lower alkyl sulfonyl (e.g. C1-6 alkyl sulfonyl such as methylsulfonyl, ethylsulfonyl),
(xxvi) aryl (e.g. C6-10 aryl such as phenyl, naphthyl) or
(xxvii) aryloxy (e.g. C6-10 aryloxy such as phenyloxy, naphthyloxy).
Examples of the optionally halogenated lower alkyl are lower alkyl (e.g. C1-6 alkyl such a methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl, hexyl) optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and so on. Specific examples of the optionally halogenated lower alkyl are methyl, chloromethyl, difluoremethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2,-trifluoroethyl, propyl, 3,3,3,-trifluoropropyl, isopropyl, buthyl, 4,4,4-trifluorobuthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl, isopenthyl, neopenthyl, 5,5,5- trifluropenthyl, hexyl, 6,6,6-trifluorohexyl and so on.
Examples of the optionally halogented lower alkenyl are lower alkenyl (e.g. C2-6 alkenyl such as vinyl, propenyl, isopropenyl, 2-butene-1-yl, 4-penthene-1-yl, 5-hexene-1-yl) optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and so on.
Examples of the optionally halogenated lower alkynyl are lower alkynly (e.g. C2-6 alkynly such as 2-butyne1-yl, 4- pentyne-1-yl, 5-hexyne-1-yl) optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and so on.
Examples of the optionally halogenated lower alkoxy are lower alkoxy (e.g. C1-6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, n-buthoxy, isobuthoxy, sec-buthoxy, tert-cuthoxy) optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and so on. Specific examples of the optionally halogenated lower alkoxy are methoxy, difluoromethoxy, tirfluoromethoxy, ethoxy, 2,2,2-trifluorobuthoxy, n-propoxy, isopropoxy, n-butoxy, 4,4,4-trifluorobuthoxy, isobuthoxy, sec-buthoxy, penthyloxy, hexyloxy and so on.
Examples of the optionally halogenated lower alkylthio are lower alkylthio (e.g. C1-6 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n-buthylthio, isobuthylthio, sec-buthylthio, tert-buthylthio) optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and so on. Specific examples of the optionally halogenated lower alkylthio are methylthio, difluromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, buthylthio, 4,4,4-trifluorobuthylthio, penthylthio, hexylthio and so on.
Examples of the acylamino are xe2x80x94NHCOOR5, xe2x80x94NHCOHNR5, xe2x80x94NHCOR5 or xe2x80x94NHSO2R5 wherin R5 is a hydrocarbon group.
Examples of the hydrocarbon group represented by R5 is a group formed by removing one hydrogen atom from the hydrocarbon compound and so on. Specific examples are a linear or cyclic hydrocarbon group such as an alkyl group, an alkenyl group, an alkynyl group a cycloalkyl group, an aryl group an ararkyl group and so on. Of them, a C1-16 chain ( linear or branched) or cyclic hydrocarbon group, and more preferable examples are
(a) alkyl group, preferably lower alkyl group (e.g. C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl, hexyl),
(b) alkenyl group, preferably lower alkenyl group (e.g. C2-6 alkenyl such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl),
(c) alkynly gorup, preferably lower alkynly (e.g. C2-6 alkynly such as propalgyl, ethynyl, butynyl, 1-hexynyl),
(d) cycloalkyl group, preferably lower cycloalkyl (e.g. C3-6 cycloalkyl such as cyclopropyl, cyclobuthyl, cyclopenthyl, cyclohexyl which may condense with a benzene ring optionally having 1 to 3 lowe alkoxys (e.g. C1-6 alkoxy such as methoxy)).
(e) an aryl group (e.g. C6-14 aryl group such as phenyl, tryl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, 1-antryl, 2-antryl, 3-antryl, 1-phenantryl, 2-phenantryl, 3-phenantryl, 4-phenantryl or 9-phenantryl, preferably phenyl),
(f) an ararkly group (e.g. C7-16 aralkyl group such as benzyl, phenetyl, diphenylmethyl, 1-napthylmethyl, 2-naphtylmethyl, 2phenylethyl, 2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbuthyl or 5phenylpenthyl, preferably benzyl).
In the above mentioned formula, preferable examples of the substituents of the xe2x80x9chomo- or hetero-cycle represented by the Axe2x80x2 are a halogen atom, an optionally halogenated lower alkyl group (preferably methyl), an optionally halogenated lower alkoxy group (preferably methoxy), a lower alkylenedioxy group (preferably methylendedioxy) or a hydroxy group, and more preferable examples are a lower alkoxy (preferably methoxy), a lower alkylenedixoy group (preferably methylenedioxy) and so on.
Preferable examples of the ring Axe2x80x2 are a homocycle which may be substituted, and more preferable examples are a benzene ring which may be substituted and so on. Specifically, the above mentioned preferable examples of the ring A are also used as preferable examples of the ring A.
In the above mentioned formula, Examples of the homocycle and heterocycle represented by the ring B are the homocycle and heterocycle of the xe2x80x9chomo- or hetero-cycle which may be substituted by a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy groupxe2x80x9d represented by the ring A.
In the above mentioned formula, Examples of the substituents of the xe2x80x9chomo- or hetero-cycle which may be substituted xe2x80x9d represented by the ring B are the same those of the substituents of the xe2x80x9chomo- or hetero-cycle which may be substitutedxe2x80x9d represented by the ring Axe2x80x2.
Preferable examples of the substituents of the xe2x80x9chomo- or hetero-cycle which may be substitutedxe2x80x9d represented by the ring B are (i) a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), (ii) a lower alkylenedioxy group (e.g. C1-3 alkylenedioxy such s methylenedioxy and ethylenedioxy, etc), (iii) an optionally halogenated lower alkyl group (e.g. optionally halogenated C1-6 alkyl such as methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bbromoethyl, 2,2,2-trifluroethyl, propyl, 3,3,3-triflluropropyl, isopropyl, buthyl, 4,4,4-triflurobuthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl, isopenthyl, neopenthyl, 5,5,5trifluoropenthyl, hexyl, 6,6,6-trifluorhexyl and so on, preferably methyl and trifluoromethyl), (iv) an optionally halogenated lower alkoxy (e.g. Optionally halogenated C1-6 alkoxy such as methoxy, difluoromethoxy, trifluromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-buthoxy, 4,4,4-triflurobutoxy, isobuthoxy, sec-buthoxy, penthyloxy, hexyloxy and so on, preferably methoxy), and so on.
Preferable examples of the ring B are a benzene ring which may be substituted. More preferable examples are (i) a C6-12 aromatic hydrocarbon ring (preferably, a benzene ring) which may be substituted by a group selected from the group consisting of a halogen atom, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy and C1-3 alkylenedioxy or (ii) a 5 to 8 membered heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms and the 5 to 8 membered heterocycle may be substituted by C1-6 alkyl, and so on.
In the above mentioned formula, X represents a methyne group which may be substituted or N(O)m (M is 0 or 1).
In the above mentioned formula examples of the xe2x80x9cmethyne group which may be substituted xe2x80x9d represented by X are CR6 wherein R6 is a hydrogen atom, (e.g. fluorine, chlorine, bromine, iodoine), a hydrocarbon group which may be substituted or a hydroxy group which may be substituted, and so on.
Examples of the hydrocarbon group represented by R6 are the hydrocarbon group represented by the above mentioned R5, and more preferable examples are a lower alkyl group such as methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl, penthyl, hexyl and so on.
Examples of the substituents of the hydrocarbon group represented by R6 are the substituents of the homo- or hetero-cycle represented by the above mentioned ring Axe2x80x2, and so on.
The hydroxy group which may be substituted represented by R6 is (i) a hydroxy group or (ii) a hydroxy group having one group such as the above mentioned hydrocarbon group which may have substituents instead of a hydrogen atom of the hydroxy group. Specifically, the above mentioned xe2x80x94OR6xe2x80x3, etc. are used, and preferable examples are a hydroxy group or a hydroxy group having one group such as a lower alkyl group which may be substituted. Examples of the lower alkyl group are a linear or branched C1-6 alkyl group (e.g. methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl, hexyl, etc.), and so on. Examples of the substituents of the lower alkyl group are the substituents of the homo- or hetero-cycle represented by the above mentioned ring Axe2x80x2.
Preferable examples of X are a methyne group which may be substituted by C1-6 alkyl or N, and more preferable examples are CH, Cxe2x80x94CH3, N and so on.
In the above mentioned formula, R1 represents an amino group which may be substituted. Examples of the substituents of the amino group are a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, an acyl group and so on. And, the amino group which may be substituted includes a nitrogen-containing heterocyclic group which has a binding site on a ring-component nitrogen atom, and the nitrogen-containing heterocyclic group may have substituents.
Examples of the hydrocarbon group of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d are the hydrocarbon goroup of the xe2x80x9chomo- or hetero-cycle which may be substitutedxe2x80x9d represented by the above mentioned R5 and so on.
Exampales of the substituents of the hydrocarbon group are the substituents of the homo- or hetero-cycle represented by the above mentioned ring Axe2x80x2.
Examples of the hydroxy group which may be substituted are the xe2x80x9chydroxy group which may be substitutedxe2x80x9d represented by the above mentioned R6, and so on.
Examples of the acyl group are xe2x80x94(Cxe2x95x90O)xe2x80x94R7, xe2x80x94SO2xe2x80x94R7, xe2x80x94SOxe2x80x94R7, xe2x80x94(Cxe2x95x90O)NR8R7, xe2x80x94(Cxe2x95x90O)Oxe2x80x94R7, xe2x80x94(Cxe2x95x90S)Oxe2x80x94R7 or xe2x80x94(Cxe2x95x90S)NR8R7 wherein R7 is a hydrogen atom or a hydrocarbon group which may be substituted and R8 is a hydrogen atom or a lower alkyl group (e.g. a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, tert-buthyl, penthyl, hexyl and so on, preferably a C1-3 alkyl such as methyl, ethyl, propyl, isopropyl and so on). Of them, xe2x80x94(Cxe2x95x90O)xe2x80x94R7, xe2x80x94SO2xe2x80x94R7, xe2x80x94SOxe2x80x94R7, xe2x80x94(Cxe2x95x90O)NR8R7, xe2x80x94(Cxe2x95x90O)Oxe2x80x94R7 are preferred, and xe2x80x94(Cxe2x95x90O)xe2x80x94R7 is more preferred.
Examples of the hydrocarbon group represented by R7 is a group formed by removing one hydrogen from atom from the hydrocarbon compound. Specific examples are chained (linear or branched) or cyclic hydrocarbon group such as an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, an ararkyl group and so on. Specifically, the hydrocarbon group represented by R5, etc. are used. Of them, a C1-16 linear or cyclic hydrocarbon group, etc. are preferred and a lower (C1-6) alkyl group, etc. are more preferred.
Examples of the substituents of the hydrocarbon group represented by R7 are the substituents of the xe2x80x9chomo- or hetero-cycle which may be substitutedxe2x80x9d represented by the ring Axe2x80x2, and so on.
Examples of the nitrogen-containing heterocyclic group represented by R1, are a group formed by removing a hydrogen atom from a nitrogen atom of a 5 to 9 membered nitrogen-containing heterocyclic which may have 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms and one nitrogen atom, and so on.
Specifically, 
are preferably used.
Examples of the substituents of the nitrogen-containing heterocyclic group are the substituents of the homo- or hetero-cycle which may be substituted represented by the above mentioned ring Axe2x80x2.
Preferable examples of the amino group which may be substituted represented by R1 are a group represented by the formula: 
wherein R3 and R4 is the same or different and are independently a hydrogen atom, a hydroxy group which may be substituted, a lower alkyl group which may be substituted, or acyl group, an aryl group which may be substituted or an aralkyl group which may be substituted, or R3 and R4 may combine with an adjacent nitrogen atom and form a nitrogen-containing heterocyclic group which may be substituted, and so on. Of them, a group wherein R3 and R4 is the same or different and are independently a hydrogen atom, a hydroxy group which may be substituted, a lower alkyl group which may be substituted or an acyl group, or R3 and R4 may combine with an adjacent nitrogen atom and form a nitrogen-containing heterocyclic group which may be substituted, etc. are preferred.
Examples of the hydroxy group which may be substituted represented by R3 and R4 are the hydroxy group which may be substituted represented by R6, etc.
Examples of the lower alkyl group represented by R3 and R4 are a linear or branched C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl and hexyl. Examples of the substituents of the lower alkyl group are the substituents of the homo- or hetero-cycle which may be substituted represented by the above mentioned ring Axe2x80x2.
Examples of the acyl group represented by R3 and R4 are the above mentioned acyl group which is the substituents of the amino group which may be substituted represented by R1.
Examples of the nitrogen-containing heterocyclic group formed by R3, R4 and the adjacent nitrogen atom are a group formed by removing a hydrogen atom from a nitrogen atom of a 5 to 9 membered nitrogen-containing heterocyclic which may have 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms and one nitrogen atom, and so on.
Specifically, 
are preferably used.
Examples of the substituents of the nitrogen-containing heterocyclic group are the substituents of the xe2x80x9chomo- or hetero-cycle which may be substitutedxe2x80x9d represented by the above mentioned ring Axe2x80x2, and so on.
Preferable examples of R3 to R4 are the same or different and are independently a hydrogen atom or a lower alkyl group which may be substituted, and so on.
Particularly, R3 is a hydrogen atom or a C1-6 alkyl group, and R4 is (i) a hydrogen atom or (ii) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carboxyl, C1-6 alkoxy-carbonyl, amino and mono- or di-C1-6 alkyl amino, (iii) a C6-14 aryl group which may be substituted by C1-6 alkoxy or (iv) a C7-16 aralkyl group which may be substituted by C1-6 alkoxy or C1-6 acylamino, or R3 and R4 may combine with an adjacent nitrogen atom and form a 5 to 8 membered nitrogen-containing heterocyclic group which may be substituted by C7-16 aralkyl (e.g., benzyl).
In the above mentioned formula, R2 represents a hydrogen atom or a lower alkyl group which may be substituted.
Examples of the lower alkyl group represented by R2 are a linear or branched C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl and hexyl. Examples of the substituents of the lower alkyl group represented by R2 are the substituents of the xe2x80x9chomo- or hetero-cycle which may have substituentsxe2x80x9d represented by the above mentioned ring Axe2x80x2, and a hydroxy group is particularly preferred.
Preferable examples of R2 are (i) a hydrogen atom or (ii) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carbamoyl optionally having C1-6 alkyl and amino optionally having C1-6 alkyl, and more preferable examples are a hydrogen atom, a C1-6 alkyl group which may be substituted by hydroxy, and so on.
Preferable examples of the compound (I) or (II) are compounds wherein R1 is a group represented by the formula: 
wherein R3 is a hydrogen atom or a C1-6 alkyl group, and R4xe2x80x2 is (i) a hydrogen atom, (ii) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carboxyl, C1-6 alkoxy-carbonyl, amino and mono- or di-C1-6 alkylamino, (iii) a C6-14 aryl (e.g., phenyl) group which may be substituted by C1-6 alkoxy or (iv) a C7-16 aralkyl group (e.g., benzyl) which may be substituted by C1-6 alkoxy or C1-6 acylamino, or R3xe2x80x2 and R4xe2x80x2 may combine with an adjacent nitrogen atom and form a 5 to 8 membered nitrogen-containing heterocyclic group which may be substituted by C7-16 aralkyl (e.g., benzyl); R2 is (i) a hydrogen atom or (ii) a C1-6 alkyl group which may be substituted selected from the group consisting of hydroxy, carbamoyl optionally having C1-6 alkyl and amino optionally having C1-6 alkyl; X is a methyne group which may be substituted by C1-6 alkyl or N(O)m (m is 0 or 1); the ring A is a C6-12 aromatic hydrocarbon ring (e.g., a benzene ring) which is substituted by a group selected from the group consisting of a halogen atom, C1-6 alkyl, C1-6 alkoxy and C1-3 alkylenedioxy; and the ring B is (i) a C6-12 aromatic hydrocarbon ring (e.g., a benzyne ring) which may be substituted by a group selected from the group consisting of a halogen atom, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy and C1-3 alkylenedioxy or (ii) a 5 to 8 membered heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms and the a 5 to 8 membered heterocycle may be substituted by C1-6 alkyl, and so on.
More preferable examples of the compound (I) or (II) are compounds wherein R1 is a group represented by the formula: 
wherein R3xe2x80x3 is a hydrogen atom and R4xe2x80x3 is a hydrogen atom or a C7-16 aralkyl group (e.g., a benzyl group) which may be substituted by C1-6 alkoxy; R2 is a hydrogen atom or a C1-6 alkyl group which may be substituted by hydroxy; X is a methyne group or N; the ring A is a C6-12 aromatic hydrocarbon ring (e.g., a benzene ring) which is substituted by C1-6 alkoxy or C1-3 alkylenedioxy; and the ring B is a C6-12 aromatic hydrocarbon ring (e.g., a benzene ring) which may be substituted by a group selected from the group consisting of a halogen atom, C1-6 alkoxy and C1-3 alkylenedioxy, and so on.
More specifically, preferable examples of the compound (I) or (II) are
N-methyl-9-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxamide or a salt thereof,
N-methyl-8-(1,3-benzodioxole-5-yl)-7-hydroxymethyl-naphtho[2,3-d]-1,3-dioxole-6-carboxamide or a salt thereof,
9-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-1,3-dioxolo [4,5-f]quinoline-7-carboxamide or a salt thereof,
N-methyl-4-(1,3-benzodioxole-5-yl)-6,7-diethoxy-3-hydroxymethyl-napthalene-2-carboxamide or a salt thereof,
9-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide or a salt thereof,
9-(1,3-benzodioxole-5-yl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo [4,5-f]quinoline-7-carboxamide or a salt thereof,
9-(4-fluorophenyl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo [4,5-f]quinoline-7-carboxamide or a salt thereof, and so on.
The compound (I) or compound (II) of the present invention or a salt thereof (hereinafter simply referred to as the compound (I) or the compound (II)) can be produced by a variety of methods; representative examples are shown in schemes 1 and 2 below.
Note that in the following description of production methods, the starting material compound and reaction product may form a salt that does not hamper the reaction.
Examples of the xe2x80x9csalt that does not hamper the reactionxe2x80x9d are the same salts as those of compound (I) or those of compound (II) below.
Of the compounds included in the compound (I) or the compound (II) wherein X is N(O)m (m represents 0 to 1), those wherein m is 1 or a salt thereof can be produced by a known chemical oxidizing reaction [e.g., Chemistry of the Heterocyclic N-Oxide, pp. 22-60 (1971), Academic Press, London and New York, or G. Jones ed., xe2x80x9cQuinolines part 1,xe2x80x9d John Wiley and Sons, Chapter 1, pp. 61-62 (1977)] or a modification thereof at an appropriate stage where the compound occurs as a compound wherein m is 0 or a salt thereof or as a production intermediate thereof.
Of the compounds included in the compound (I) or the compound (II), a compound wherein R2 is a hydrogen atom and X is a methine group which may be substituted, namely a compound (XI), or compound (XIxe2x80x2), can, for example, be produced by the method shown by scheme 1 below. 
With respect to the compounds (IV) to (XI) or the compounds (IVxe2x80x2) to (XIxe2x80x2) in scheme 1 above, E represents a hydrogen atom or a halogen atom (e.g., fluorine, chlorine); R9 represents a lower alkyl group (e.g., methyl, ethyl); the other symbols have the same definitions as those shown above.
Of the compounds included in the compound (I), a compound wherein ring A is a benzene ring which is substituted by a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group, R2 is a hydrogen atom, and X is N, can be produced by carrying out a reaction by a commonly known method (E. C. Taylor et al., Journal of Organic Chemistry, Vol. 32, pp. 1899-1900 (1967)), using a compound represented by the formula: 
wherein R10 represents a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group present at any possible position on the benzene ring as a substituent, the number of substituents being 1 to 4; the other symbols have the same definitions as those shown above; in place of compound (VI) in scheme 1 above.
Of the compounds included in the compound (I) or the compound (II), a compound wherein R2 is a lower alkyl group that may have a substituent, namely a compound (XIV) or compound (XIVxe2x80x2), can, for example, be produced by the method shown by scheme 2 below. 
With respect to the compounds (XII) to (XIV) or compounds (XIIxe2x80x2) to (XIVxe2x80x2) in scheme 2 above, R11 represents a lower alkyl group that may have a substituent; the other symbols have the same definitions as those shown above.
Also, the compound (I) or compound (II) can also be synthesized by a compound represented by formula (XV) or (XVxe2x80x2) by the method shown in scheme 3 below. 
With respect to the compounds (XV) to (XVxe2x80x2) in scheme 3 above, R12 represents a hydrogen atom or a lower alkyl group that may be substituted; the other symbols have the same definitions as those shown above.
Examples of the lower alkyl group represented by R9 to R12 are a linear or branched C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
Examples of the substituent of the lower alkyl group the substituent of the homo- or hetero-cycle represented by the mentioned above ring Axe2x80x2.
Provided that, R11 does not include a hydroxymethyl group.
The respective reactions of schemes 1 to 3 in the above-described production methods are hereinafter described in more detail.
Reaction processes 1 and 2 can be carried out in accordance with commonly known methods (e.g., J. G. Smith et al., Journal of Organic Chemistry, Vol. 53, pp. 2,942-2,953 (1988); T. Kuroda et al., Journal of Chemical Society Chemical Communications, pp. 1,635-1,636 (1991); T. Kuroda et al., Journal of Organic Chemistry, Vol. 59, pp. 7,353-7,357 (1994)).
Specifically, in reaction process 1, the compound [VI] or compound [VIxe2x80x2] is produced by treating the compound [VI] or compound [IVxe2x80x2] with a base to produce a dianion, and condensing it with the compound [V].
The base used is exemplified by alkyllithiums; preferable alkyllithiums include, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium and phenyllithium, with greater preference given to n-butyllithium. The amount of alkyllithium used is normally 2 to 10 mol, preferably 2 to 3 mol, per mol of the compound [IV] or compound [IVxe2x80x2].
The amount of the compound [V] used is normally 0.5 to 10 mol, preferably 1 to 3 mol, per mol of the compound [IV] or compound [IVxe2x80x2].
Also, said reaction can be advantageously carried out in a solvent. The solvent used is a solvent that does not adversely affect the reaction. Useful solvents include, for example, hydrocarbons (e.g., pentane, hexane, cyclohexane, benzene), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane), amides (e.g., hexamethylphosphoric triamide) and ureas (e.g., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine). These solvents may be used singly, or in mixtures of 2 or more kinds mixed in appropriate ratios or as mixed solvents with water. The amount of solvents used is normally 1 to 100 milliliters, preferably 5 to 20 milliliters, per gram of the compound [IV] or compound [IVxe2x80x2].
Reaction temperature for the base and the compound [IV] or compound [IVxe2x80x2] is normally xe2x88x9272xc2x0 C. to 200xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C. Reaction time is normally 30 minutes to 24 hours, preferably 30 minutes to 12 hours.
Reaction temperature for the subsequent condensation with the compound [V] is normally xe2x88x9272xc2x0 C. to 200xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C. Reaction time is normally 30 minutes to 72 hours, preferably 30 minutes to 18 hours.
In reaction process 2, the compound [VIII] or compound [VIIIxe2x80x2] is produced by treating the compound [VI] or compound [VIxe2x80x2] with an acid produce a condensed furan derivative in the reaction system, and condensing it with the compound [VII].
The acid used is an inorganic acid or an organic acid; preferable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and polyphosphoric acid. Preferable organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. The amount of acid used is normally 0.01 to 10 mol, preferably 0.03 to 2 mol, per mol of the compound [VI] or compound [VIxe2x80x2].
The amount of the compound [VII] used is normally 1 to 10 mol, preferably 1 to 3 mol, per mol of the compound [IV] or compound [VIxe2x80x2].
Also, said reaction can be advantageously carried out in a solvent. The solvent used is a solvent that does not adversely affect the reaction; useful solvents include, for example, hydrocarbons (e.g., pentane, hexane, cyclohexane, benzene, toluene), lower alcohols (e.g., methanol, ethanol, propanol), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane) and halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane). Also, when the above-mentioned acids are liquid, they may be used as solvents. These solvents may be used singly, or in mixtures of 2 or more kinds mixed in appropriate ratios of as mixed solvents with water. The amount of solvents used is normally 1 to 100 milliliters, preferably 5 to 20 milliliters, per gram of the compound [VI] or compound [VIxe2x80x2].
Reaction temperature is normally xe2x88x9220xc2x0 C., preferably 25xc2x0 C. to 150xc2x0 C.
Reaction time is normally 30 minutes to 24 hours, preferably 30 minutes to 12 hours.
In reaction process 3, the compound (IX) or compound (IXxe2x80x2) is produced by subjecting the compound (VIII) or compound (VIIIxe2x80x2) to a hydrolytic reaction.
Said hydrolytic reaction can, for example, be carried out using a commonly known method (S. R. Sandler and W. Karo, xe2x80x9cOrganic Functional Group Preparations I,xe2x80x9d 2nd ed., Academic Press (1983), Chapter 9 (pp. 271-273)).
Also, when said hydrolytic reaction is carried out under acidic conditions, reaction process 4 can take place simultaneously with reaction process 3 to yield the compound (X) or compound (Xxe2x80x2).
In reaction process 4, the compound (X) or compound (Xxe2x80x2) is produced by subjecting the compound (IX) or compound (IXxe2x80x2) to an aromatizing reaction for simultaneous dehydration and decarboxylation.
Although said aromatizing reaction is normally carried out by treating the compound (IX) or compound (IXxe2x80x2) with an acid, it can also be carried out by keeping standing or heating the compound (IX) or compound (IXxe2x80x2) under neutral conditions.
The acid used is an inorganic acid or an organic acid; preferable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and polyphosphoric acid. Preferable organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. The amount of acid used is normally 0.01 to 10 mol, preferably 0.03 to 2 mol, per mol of the compound (IX) or compound (IXxe2x80x2).
Also, said reaction can be advantageously carried out in a solvent. The solvent used is a solvent that does not adversely; affect the reaction; useful solvents include, for example, hydrocarbons (e.g., pentane, hexane, cyclohexane, benzene), lower alcohols (e.g., methanol, ethanol, propanol), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane) and halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane). Also, when the above-mentioned acids are liquid, they may be used as solvents. These solvents may be used singly, or in mixtures of 2 or more kinds mixed in appropriate ratios or as mixed solvents with water. The amount of solvent used is normally 1 to 100 milliliters, preferably 5 to 20 milliliters, per gram of the compound (IX) or compound (IXxe2x80x2). Reaction temperature is normally about xe2x88x9220xc2x0 C. to about 200xc2x0 C., preferably about 25xc2x0 C. to about 150xc2x0 C. Reaction time is normally 30 minutes to 24 hours, preferably 30 minutes to 12 hours.
In reaction process 5, the compound (XI) or compound (XIxe2x80x2) is produced by subjecting the compound (X) or compound (Xxe2x80x2) to an amidating reaction, followed by an acylating reaction as necessary.
Said amidating reaction can, for example, be carried out using a commonly known method (S. R. Sandler and W. Karo, xe2x80x9cOrganic Functional Group Preparations I,xe2x80x9d 2nd ed., Academic Press (1983), Chapter 11 (pp. 315-358)).
Said acylating reaction can, for example, be carried out using a commonly known method (S. R. Sandler and W. Karo, xe2x80x9cOrganic Functional Group Preparations I,xe2x80x9d 2nd ed., Academic Press (1983), Chapter 7 (pp. 281-313)).
In reaction process 6, the compound [XIII] or compound [XIIIxe2x80x2] is produced by subjecting the compound [XII] or compound [XIIxe2x80x2] to a ring-opening reaction, followed by an acylating reaction as necessary.
The compound [XII] or compound [XIIxe2x80x2], serving as the starting material, may, for example, be a lactone compound produced by commonly known methods (R. S. Burden et al. Journal of the Chemical Society Section C, pp. 693-701, 1969; Archives of Pharmacology, 328(9), pp. 640-644, 1995; Indian Journal of Chemistry, Section B: Org. Chem. Include. Med. Chem., 33B(9), pp. 839-846, 1994; Indian Journal of Chemistry, Section B: 31B(7), pp. 401-406, 1992; Chemical and Pharmaceutical Bulletin, 32(1), pp. 31-37, 1984; Journal of the Chemical Society Section C, (11), pp. 2,091-2,094, 1971; Phytochemistry 29(9), pp. 2,991-2,993, 1990; Journal of Natural Products, 43(4), pp. 482-486, 1980; M. Anazini et al., Heterocycles, Vol. 38, pp. 103-111, 1994, etc.) or modification thereof.
The ring-opening reaction is carried out by reacting the compound [XII] or compound [XIIxe2x80x2] with ammonia or an amine derivative represented by HR1 (R1 has the same definition as that shown above).
The ammonia used is aqueous ammonia or gaseous or liquid ammonia.
The amount of ammonia or amine derivative used is normally 1 mol to about 100 mol, preferably 2 to 10 mol, per mol of the compound [XII] or compound [XIIxe2x80x2].
The reaction can be advantageously carried out in a solvent. The solvent used is a solvent that does not adversely affect the reaction; useful solvents include for example, hydrocarbons (e.g., pentane, hexane, cyclohexane, benzene), lower alcohols (e.g., methanol, ethanol, propanol), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane), amides (e.g., N,N-dimethylformamide, hexamethylphosphoric triamide) and ureas (e.g., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine). Also, when the amine derivative represented by HR1 (R1 has the same definition as that shown above) is liquid, it can also be used as a solvent. These solvents may be used singly, or in mixtures of 2 or more kinds mixed in appropriate ratios or as mixed solvents with water. The amount of solvent used is normally 1 to 100 milliliters, preferably 5 to 20 milliliters, per gram of the compound [XII] or compound [XIIxe2x80x2]. Reaction temperature is normally xe2x88x9220xc2x0 C. to 200xc2x0 C., preferably 25xc2x0 C. to 150xc2x0 C.; in some cases, the reaction can be advantageously carried out in a sealed tube.
Also, when the R1 in HR1 (R1 has the same definition as that shown above) is an acylated amino group, said reaction can be advantageously proceeded in the presence of a base.
The base used is exemplified by alkyllithium reagents (e.g., methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, preferably n-butyllithium); inorganic bases (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, metallic sodium) and organic bases (e.g., sodium methoxide, sodium ethoxide, triethylamine, pyridine, diethylisopropylamine). The amount of base used is normally 1 to about 10 mol, preferably 1 to 2 mol, per mol of the compound [XII] or compound [XIIxe2x80x2].
Reaction time is normally 30 minutes to 1 week, preferably 30 minutes to 4 days.
The acylating reaction carried out after the ring-opening reaction as necessary can, for example, be carried out using the method described for reaction process 5.
In reaction process 7, the compound (XIV) or compound (XIVxe2x80x2) is produced by subjecting the compound (XIII) or compound (XIIIxe2x80x2) to a functional group-converting reaction, a carbon-adding reaction or an appropriate combination thereof.
Said functional group-converting reaction or carbon-adding reaction can, for example, be carried out by commonly known methods (J. Mathieu and J. Weil-Raynal, xe2x80x9cFormation of Cxe2x80x94C Bonds I-III, xe2x80x9d George Thieme Publishers, Stuttgart (1973, 1975, 1979); S. R. Sandler and W. Karo, xe2x80x9cOrganic Functional Group Preparations I-III,xe2x80x9d 2nd ed., Academic Press (1983, 1986, 1989) etc.).
In reaction process 8, the compound (I) or compound (II) is produced by subjecting the compound (XV) or compound (XVxe2x80x2) to an amidating reaction, followed by an acylating reaction as necessary.
The compound (XV) or compound (XVxe2x80x2), serving as the starting material, may, for example, be a carboxylic acid derivative produced by commonly known methods (e.g., G. Jones ed., xe2x80x9cQuinolines Part 1, xe2x80x9d John Wiley and Sons (1977), Chapter 2 (pp. 93-318); L. S. El-Assal et al., Journal of Chemical Society, pp. 1,658-1,662, (1961); D. Delorme et al., Journal of Medicinal Chemistry, Vol. 39, pp. 3,951-3,970, (1996)) or modifications thereof.
The amidating reaction can, for example, be carried out using a commonly known method (S. R. Sandler and W. Karo, xe2x80x9cOrganic Functional Group Preparations I,xe2x80x9d 2nd ed., Academic Press (1983)), Chapter 11 (pp. 315-358)).
The acylating reaction can, for example, be carried out using the method described for reaction process 5.
Also, when the desired compound is produced by the methods shown by schemes 1 through 3 above, and provided that the substituents or rings A and B in the compounds (IV) through (XV) and the compounds (IVxe2x80x2) through (XVxe2x80x2) contain a functional group such as a hydroxyl group, an amino group, a mono-C1-6 alkylamino group, a ketone, a carboxyl group or a tetrazolyl group, for example, these functional groups may be protected; regarding the kind of protecting group, and methods of protection and deprotection, a commonly known method (T. W. Green and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d 2nd ed., John Wiley and Sons, Inc., (1991)) etc. are used.
The thus-obtained compound (I), compound (II) or a salt thereof can be isolated and purified by commonly known means (e.g., redissolution, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography).
Also, the salt of the compound (I) or compound (II) of the present invention is preferably a pharmaceutically acceptable salt, exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Preferable salts with inorganic bases include, for example, alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., calcium salt, magnesium salt), aluminum salt and ammonium salt. Preferable salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine etc.
Preferable salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid etc.
Preferable salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid etc.
Preferable salts with basic amino acids include, for example, salts with arginine, lysine, ornithine etc.
Preferable salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid etc. Also, when the desired product is obtained in free form, it may be converted to a salt by a conventional method; when the desired product is obtained as a salt, it may be converted to the free compound by a conventional method.
The compound (I) or compound (II) of the present invention or a salt thereof may be a hydrate or non-hydrate.
The compound (I) or compound (II) or a salt thereof may be isolated and purified by commonly known means, e.g., solvent extraction, liquid nature conversion, redissolution, crystallization, recrystallization and chromatography. Also, although the starting compound for the compound (I) or compound (II) or a salt thereof may be isolated and purified by the same known means as those shown above, it may be used as a starting material for the next process as a reaction mixture as is without isolation.
When the compound (I) or compound (II) of the present invention or a salt thereof contains an optical isomer, a stereoisomer, a position isomer or a rotational isomer, these isomers are also included in the scope of the compounds of the present invention, and each can be obtained as a single product by commonly known means of synthesis or separation. For example, when an optical isomer is present in the compound of the present invention, the optical isomer resolved from said compound is also included in the scope of the present invention.
An optical isomer can be produced by commonly known methods. Specifically, an optical isomer is obtained by using an optically active synthesis intermediate or by optically resolving the final racemate mixture by a conventional method.
Useful methods of optical resolution include commonly known methods, e.g., the fractional recrystallization method, chiral column method and diastereomer method described below.
(1) Fractional recrystallization method
A salt of a racemate and an optically active compound is formed and separated by the fractional recrystallization method to yield a free optical isomer via a neutralization process is desired.
(2) Chiral column method
A racemate or a salt thereof is applied to a column for optical isomer separation (chiral column) to separate it. In the case of liquid chromatography, for example, optical isomers are separated by adding a mixture thereof to a chiral column such as ENANTIO-OVm (produced by Tosoh Corporation), and developing it in water, various buffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol, acetonitrile) as a simple or mixed solution. Also, in the case of gas chromatography, for example, a chiral column such as CP-Chirasil-DeX CB (produced by GL Science) is used to separate optical isomers.
(3) Diastereomer method
A diastereomer mixture, prepared from a racemate mixture using an optically active reagent and chemical reaction, is treated by ordinary means of separation (e.g., fractional recrystallization, chromatography) etc. to obtain a single substance, after which the optically active reagent moiety is cut off by a chemical treatment such as hydrolysis reaction. When the compound of the present invention has a hydroxyl group or a primary or secondary amino group in the molecular structure thereof, an ester or amide diastereomer, respectively, is obtained by subjecting said compound, an optically active organic acid (e.g., MPTA [xcex1-methoxy-xcex1-(trifluoromethyl)phenylacetic acid], (xe2x88x92)-methoxyacetic acid) etc. to a condensation reaction. On the other hand, when the compound (I) of the present invention has a carboxylic acid group, an ester or amide diastereomer, respectively, is obtained by subjecting said compound and an optically active amine or an alcohol reagent to a condensation reaction. The diastereomer separated is converted to an optical isomer of the original compound by an acid hydrolysis or basic hydrolysis reaction.
The cell differentiation induction factors serving as targets of the present invention include factors which induce a character characteristic of the process of differentiation of undifferentiated precursors of cells which maintain living body function in particular tissue, such as osteoblasts and neurons, e.g., factors belonging to the TGF-xcex2 superfamily such as bone morphogenetic protein, neurotrophic factors, transforming growth factor (TGF)-xcex2 and activin, factors belonging to the FGF superfamily such as basic fibroblast growth factor (bFGF) and acidic fibroblast growth factor (aFGF), factors belonging to the neuropoietic cytokine family such as leukemia inhibitory factor (LIF, or also called cholinergic differentiation factor (CDF)) and ciliary neurotrophic factor (CNTF), interleukin 1 (IL-1, hereinafter similarly abbreviated), IL-2, IL-3, IL-5, IL-6, IL-7, IL-9, IL-11, tumor necrosis factor-xcex1 (TNF-xcex1) and interferon-xcex3 (INF-xcex3), with preference given to bone morphogenetic protein and neurotrophic factors.
Bone morphogenetic factors include members of the MBP family of proteins which promote osteogenesis and chondrogenesis, such as BMP-2, -4, -5, -6, -8, -9, -10, -11 and -12, with preference given to BMP-2, -4, -6 and -7. BMP may be a homo-dimer of each of the above-mentioned factors or a hetero-dimer consisting of any possible combination thereof.
Neurotrophic factors include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophic-3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF), with preference given to the NGF family.
The compound (I) or compound (II) of the present invention or a salt thereof can be safely administered orally or non-orally (e.g., topical, rectal and intravenous administration), as such or in the form of pharmaceutical compositions formulated with a pharmaceutically acceptable carrier, e.g., tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), syrups, emulsions, suspensions, injectable preparations (e.g., subcutaneous, intradermal, intramuscular injections), suppositories and sustained-release preparations, in accordance with a commonly known method. The content of compound (I), compound (II) or a salt thereof in the preparation of the present invention 0.1 to 100% by weight relative to the entire preparation. Varying depending on subject of administration, route of administration, target disease etc., the daily dose of the compound (I) or (II) of the present invention or a salt thereof is normally about 0.1 to 500 mg, preferably about 1 to 100 mg, and more preferably about 5 to 100 mg, per day, based on the active ingredient, per adult (60 kg), administered in 1 to several portions per day, when it is used in a cell differentiation induction factor action agent or an enhancer for said action, for example.
Said injectable preparation is used by a commonly known method, i.e., the compound (I) or (II) or a salt thereof is used as such or in combination with a substance exhibiting cell differentiation induction factor action, e.g., BMP or neurotrophic factor. Aqueous solutions for injection include physiological saline and isotonic solutions, and may be used as necessary in combination with the suspending agents shown below. Oily liquids include sesame oil and soybean oil, and may be used in combination with the dissolution aids shown below. The injectable preparation prepared is normally filled in appropriate ampules.
Pharmacologically acceptable carriers used to produce the preparation of the present invention are various organic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders and disintegrants for solid preparations, and solvents, dissolution aids, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations. Other pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweetening agents, adsorbents and wetting agents may be used as necessary. Excipients include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose and light silicic anhydride. Lubricants include, for example, magnesium stearate, calcium stearate, talc and colloidal silica.
Binders include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, saccharose, gelatin, methyl cellulose and carboxymethl cellulose sodium.
Disintegrants include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and L-hydroxypropyl cellulose.
Solvents include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil.
Dissolution aids include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.
Suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and monostearic glycerol; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
Isotonizing agents include, for example, glucose, D-sorbitol, sodium chloride, glycerol and D-mannitol.
Buffers include, for example, buffer solutions of phosphates, acetates, carbonates, citrates etc.
Soothing agents include, for example, benzyl alcohol.
Preservatives include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
Antioxidants include, for example, sulfites and ascorbic acid.
Since a pharmaceutical composition containing the compound (I) or compound (II) or a salt thereof exhibits excellent cell differentiation-inducing action and cell differentiation-inducing factor action-enhancing action, it is useful in the treatment and prevention of various nerve diseases (e.g., diseases based on nerve degeneration, such as those in cerebrovascular dementia, senile dementia or Alzheimer""s disease; motor neuronal disease such as amyotrophic lateral scelerosis (Lou Gehrig disease); or diabetic peripheral neuropathy) or bone/joint diseases (e.g., bone fractures, osteoporosis, osteoarthritis, rheumatoid arthritis); specifically, agents for treating or preventing bone/joint diseases include, for example, osteogenesis promoters, cartilage destruction suppressors, bone fracture healing promoters or bone reconstruction promoters, when used alone or in combination with substances exhibiting cell differentiation induction factor action (e.g., BMP, neurotrophic factors).
Furthermore, because not all roles of BMP, neurotrophic factor, etc. in the living body have been clarified, it is likely that pathologic condition can be improved in other diseases by enhancing the actions of BMP, neurotrophic factors, etc. The cell differentiation-inducing action agent or cell differentiation-inducing factor action-enhancing agent of the present invention can also be used as an agent for treating or preventing such diseases associated with BMP, neurotrophic factors, etc.
The cell differentiation-inducing action agent or cell differentiation-inducing factor action-enhancing agent of the present invention can be used in the above-mentioned diseases not only in humans but also in other mammals (e.g., mice, rats, rabbits, dogs, cats, bovines, pigs).
Also, a pharmaceutical composition containing the compound (I) or compound (II) of the present invention or a salt thereof is of low toxicity and has few side effects.
The cell differentiation-inducing action agent or cell differentiation-inducing factor action-enhancing of the present invention can be mixed in a carrier for bone reconstruction as an osteogenesis promoter in bone repair and bone transplantation because it possesses potent osteogenesis-promoting activity. For example, the compound of the present invention can be used as adhered to, or contained in, artificial bones etc. prepared from metals, ceramics or high-molecular substances. The artificial bone is preferably made porous on the surface thereof to allow the cell differentiation induction factor action enhancer of the present invention to be released in living tissue upon its transplantation to a bone defect. The compound of the present invention can be adhered to, or contained in, an artificial bone by dispersing it in an appropriate dispersant, binder, diluent or the like (e.g., collagen, physiological saline, citric acid solution, acetic acid solution, hydroxyapatite, fibrin, mixture thereof) and applying it to, or impregnating it in, the artificial bone, followed by drying. Such artificial bone is transplanted to a bone defect and firmly fixed to the defect. An artificial bone fixative can be prepared by mixing the active ingredient helioxanthine with dispersants, binders, diluents, other components effective on bone regeneration (e.g., calcium), etc. that are physiologically acceptable for pharmaceutical use. The artificial bone fixative can also be used to fill in the gap between the artificial bone transplanted to the bone defect in the hose and the bone defect, without adhering it to, or containing it in, the artificial bone. It should be noted that the non-oral composition described here can also be used with an osteogenesis-promoting protein such as the BMP family adhered thereto or contained therein.
Mode of Working The Invention
The present invention is described in more detail by the following Reference Examples, Examples, Formulation Examples and Experimental Examples but they are merely illustrative and should not be construed as limiting the scope of the invention. Thus, many modifications may be made without from the scope of the invention.
In the column chromatography in the following Reference Examples and Examples, elutions (developing solvent was indicated in brackets) were carried out under thin-layer chromatography monitoring.
The TLC monitoring was carried out using Kieselgel 60F254 (layer thickness 0.25 mm, Merck) for TLC plates, the solvents which were used in the column chromatography as developers, UV detector and phosphomolyvdate color reaction for detector. As silica gel for column chromatography, Kieselgel 60 (70-230 mesh, Merck) was used. The NMR spectra represent proton NMR (1H-NMR) spectra, which were measured with Gemini 200 (produced by Varian) using tetramethylsilane either as internal or external standard and expressed in xcex4 (ppm).
The infrared absporption Spectra were recorded with IR-810 spectrophotometer (Nippon Bunko Kogyo). The melting points were determined with the Yanagimoto micromelting point meter MP-500D and the uncorrected values were shown. The xe2x80x9croom temperaturexe2x80x9d in the following Reference and Working Examples means 0xc2x0 C.-30xc2x0 C., preferably about 15xc2x0 C.-25xc2x0 C.
In the chemical formulas in the following Examples and Reference Examples, Me stands for methyl and Ms for methanesulfonyl. The other symbols or abbreviations used in the present specification have the following meanings.